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Growth, Differentiation, and Energy Metabolism in Embryos of Various Gestational Ages
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Enhanced oxidative metabolism may cause an increased production of free oxygen radicals in the embryo. This concept was recently studied in rat embryo culture in vitro.113 Supplementation of citiolone, superoxide dismutase, catalase, or glutathione peroxidase to the culture medium protected against growth retardation and embryonic malformations induced by increased glucose concentration. It was concluded that glucose causes disturbed embryonic morphogenesis in vitro by generation of free oxygen radicals.113 The notion of free oxygen radicals causing embryonic maldevelopment is also supported by the finding of such dysmorphogenesis in embryos subjected to buthionine sulfoximine, a compound which decreases the cellular levels of the antioxidant GSH.114,115 Of interest in this context are the reports suggesting a decreased oxidative defense in embryos in general,116 and in neural crest cells in particular.112
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
In line with the above findings, Benítez et al. (2016) focused on identifying TrypS inhibitors, using target-based screening of a compound library. Furthermore, Vázquez et al. (2017) discovered buthionine sulfoximine as a dual inhibitor of γECS and TrypS, which was further confirmed by the docking and over-expression experiments.
Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
Although increased GSH pools have been reported in cells resistant to phenylalanine mustard, the relationship between this increase and the development of resistance is not clear. However, this finding is of potential therapeutic interest as it is now possible to manipulate levels of this tripeptide in vivo. Indeed, buthionine sulfoximine (BSO) has been shown to be a selective inhibitor of γ-glutamyl cysteine synthetase and has proven effective in inhibiting GSH synthesis and lowering intracellular GSH pools. Moreover, BSO has recently been used to reduce GSH levels in phenylalanine mustard-resistant L1210 cells.49,74 Under these conditions of decreased GSH levels, the sensitivity of resistant cells to the alkylating agent increased. Similarly, BSO has been shown to potentiate phenylalanine mustard toxicity in drug-resistant human ovarian cancer cells, both in vitro and in tumor-bearing mice.75 The clinical utility of BSO in potentiating the cytotoxicity of certain antineoplastic agents, as well as the use of esters of GSH as protecting or rescue agents, is currently being assessed.76
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
Luteolin (3′,4′,5,7-tetrahydroxyflavone, Figure 11(g)), a well-known flavonoid present in many diets, supplements and herbal medicines, possesses a variety of pharmacological activities including antioxidant, anti-inflammatory, antipruritic, antimicrobial, antitumor and neuroprotection effects (Seelinger et al. 2008). As a close analog of quercetin, luteolin is oxidized by CYP3A to an electrophilic ortho-benzoquinone intermediate that can be trapped by GSH (Shi et al. 2015) (Figure 11g). Induction of CYP3A by dexamethasone enhanced luteolin-induced cytotoxicity in primary hepatocytes, whereas inhibition of CYP3A by ketoconazole inhibited formation of luteolin GSH adducts and decreased the cytotoxicity (Shi et al. 2015). Depletion of intracellular GSH by L-buthionine sulfoximine (BSO) significant enhanced the cytotoxicity. These data suggested that CYP3A-mediated ortho-benzoquinone formation followed by GSH depletion is a molecular initiating event in luteotin-induced cytotoxicity. Meantime, it is conceivable that the ortho-benzoquinone intermediate of luteolin plays a critical role in its broad pharmacological activities such as antioxidant and anticancer effects (Kang et al. 2019).
Oxidative stress impairs cGMP-dependent protein kinase activation and vasodilator-stimulated phosphoprotein serine-phosphorylation
Published in Clinical and Experimental Hypertension, 2019
Anees A. Banday, Mustafa F. Lokhandwala
Reduced vasodilation in response to endothelium-dependent vasodilators such as acetylcholine is a hallmark of endothelial dysfunction and development of hypertension (2,3). The mechanisms underlying endothelial dysfunction are likely to be multifactorial but could be due to NO degradation or defective NO signaling caused, at least in part, by oxidative stress (2,3). Previously we have shown that rats treated with L-buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, exhibited oxidative stress and increased blood pressure (17). The blood vessels from these rats showed decreased response to acetylcholine and sodium nitroprusside (SNP) (17). The reduced response to acetylcholine in hypertensive animals has been extensively studied and could be explained by a decreased bioavailability of NO, partly due to its inactivation by oxidative stress. However, the diminished response to SNP remains unknown. Therefore, the present studies were carried out in endothelium-denuded mesenteric tissue to unravel the mechanisms for oxidative stress-mediated attenuation of NO signaling (independent of NO bioavailability) in smooth muscles which could be an important contributor to the development of hypertension. Since PKG is a primary determinant of NO-mediated vasorelaxation, the present study was designed to investigate the effect of oxidative stress on PKG signaling. SD rats were treated with BSO for 3 weeks and endothelial denuded blood vessels were used to study the impairment in NO/PKG/VASP pathway in the setting of hypertension.
Transferrin-targeting redox hyperbranched poly(amido amine)-functionalized graphene oxide for sensitized chemotherapy combined with gene therapy to nasopharyngeal carcinoma
Published in Drug Delivery, 2019
Tao Liu, Jingzhen Li, Xidong Wu, Siyi Zhang, Zhongming Lu, Guanxue Li, Junzheng Li, Shaohua Chen
Glutathione (GSH) has been found to be much higher were expected level expression in tumor cells than that in normal cells, and the GSH-mediated detoxification is an important reason for the drug resistance of cancer cells (Jing et al., 2018). Therefore, many GSH-response drug delivery systems have been designed, which were expected to be degraded intracellularly due to the presence of GSH at a high concentration and then achieve the effective drug delivery and rapid drug release (Cheng et al., 2018; Ji et al., 2018; Zhu et al., 2018). Moreover, the drug sensitizers, such as buthionine sulfoximine (BSO), selectively inhibit the synthesis of GSH, have been combined with chemotherapeutic drugs and used in clinical for effective cancer therapy (Hu et al., 2018; Moghaddam et al., 2018; Zhang et al., 2018). Tang et al. have reported a drug carrier combining chemotherapeutic drug sensitization with GSH-response recently (Tang et al., 2018). They synthesized the redox hyperbranched poly(amido amine) containing disulfide bonds (HPAA) and then conjugated the antitumor drug of methotrexate. The obtained prodrug showed the self-sensibilization effect coming from the intracellular GSH consumption resulted from the HPAA segments, and showed effective tumor cell inhibition in vitro and in vivo.